The Pan-ErbB Negative Regulator Lrig1 Is an Intestinal Stem Cell Marker that Functions as a Tumor Suppressor
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Lineage mapping has identified both proliferative and quiescent intestinal stem cells, but the molecular circuitry controlling stem cell quiescence is incompletely understood. By lineage mapping, we show Lrig1, a pan-ErbB inhibitor, marks predominately noncycling, long-lived stem cells that are located at the crypt base and that, upon injury, proliferate and divide to replenish damaged crypts. Transcriptome profiling of Lrig1(+) colonic stem cells differs markedly from the profiling of highly proliferative, Lgr5(+) colonic stem cells; genes upregulated in the Lrig1(+) population include those involved in cell cycle repression and response to oxidative damage. Loss of Apc in Lrig1(+) cells leads to intestinal adenomas, and genetic ablation of Lrig1 results in heightened ErbB1-3 expression and duodenal adenomas. These results shed light on the relationship between proliferative and quiescent intestinal stem cells and support a model in which intestinal stem cell quiescence is maintained by calibrated ErbB signaling with loss of a negative regulator predisposing to neoplasia.
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Depletion of tumor suppressor LRIG1 was identified as the top hit contributing to increased cell proliferation.
“Notably, the depletion of tumor suppressor LRIG1, a negative regulator of ERBB receptor tyrosine kinases40–42, was identified as the top hit contributing to increased cell proliferation (Fig. 1D).”
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“Notably, the depletion of tumor suppressor LRIG1 , a negative regulator of ERBB receptor tyrosine kinases 40 – 42 , was identi fi ed as the top hit contributing to increased cell proliferation (Fig.”
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Self-citation
- Authors
- Powell, A. E., Wang, Y., Li, Y., Poulin, E. J., Means, A. L., Washington, M. K., Higginbotham, J. N., Juchheim, A., Prasad, N., Levy, S. E., Guo, Y., Shyr, Y., Aronow, B. J., Haigis, K. M., Franklin, J. L., & Coffey, R. J.
- Affiliations
- Vanderbilt University Medical Center (US)
- Harvard University (US)
- HudsonAlpha Institute for Biotechnology (US)
- Cincinnati Children's Hospital Medical Center (US)
- Nashville VA Medical Center (US)
- Corresponding author
- Coffey, Robert J.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 149
- Issue
- 1
- Pages
- 146-158
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3563328
- OpenAlex
- W2044022855
- Cited by
- 694
- References
- 6
- Citations by year
- 2026: 22 · 2025: 27 · 2024: 36 · 2023: 31 · 2022: 45 · 2021: 53 · 2020: 53 · 2019: 58 · 2018: 63 · 2017: 48 · 2016: 51 · 2015: 66 · 2014: 50 · 2013: 66 · 2012: 25
- FWCI
- 32.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR000077)
- National Cancer Institute (CA151566, CA46413, R01CA151566, P50CA095103, U01CA084239, R01CA046413, T32CA119925)
- National Institute of General Medical Sciences (T32GM008554)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK058404, P30DK043351)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Digestive system and related health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- Lrig1, intestinal stem cells, stem cell quiescence, tumor suppressor, ErbB signaling, APC, colonic adenoma, duodenal adenoma, Lgr5, gene expression profiling
- MeSH terms
- Adenoma, Animals, Colon, Humans, Intestinal Neoplasms, Intestine, Small, Membrane Glycoproteins, Nerve Tissue Proteins, Stem Cells, Signal Transduction, Genes, Tumor Suppressor, Gene Expression Profiling, Adenomatous Polyposis Coli Protein, Receptors, G-Protein-Coupled, Mice, ErbB Receptors
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